The disease burden of the more than 80 distinct autoimmune diseases in the United States is enormous, collectively affecting 14 to 22 million people, an estimated 5-8% of the U.S. population. In addition, an estimated 50 million people in the U.S. suffer allergies. Allergy is the fifth leading chronic disease in the U.S. among all ages, and the third most common chronic disease among children under 18 years old.
Several types of medications are available to treat allergies symptoms, including antihistamines, decongestants, corticosteroids, and others. It is estimated that the annual cost for prescription and over-the-counter medications in the U.S. to treat allergies is $11 billion.
For most autoimmune diseases, immunosuppression is the therapy of choice. Conventional agents that induce non-specific immunosuppression, such as non-steroidal anti-inflammatory drugs, glucocorticoids, and methotrexate have traditionally been the mainstay of therapy for many autoimmune diseases. While helpful, these medications are not always fully efficacious and are associated with significant toxicity when used chronically. Additionally, by non-specifically suppressing the immune system, these medications substantially increase patient susceptibility to infections.
Over the past few years, a number of new medications have become available which are able to specifically target certain arms of the immune response. While such approaches clearly represent a step forward in focusing immunosuppressive therapy, none does so in an antigen-specific manner. Consequently, these new medications still increase patient susceptibility to infections, albeit to a smaller range of organisms than non-specific immunosuppressive agents. This phenomenon is exemplified by the recent findings that tumor necrosis factor inhibitors, despite blocking the activity of only one cytokine, increase the risk of pneumonia, severe skin infections, and reactivation of prior tuberculosis.
Given the increased risk to infection that occurs when even specific facets of the immune system are inhibited, an alternative therapy for autoimmune diseases would be one that suppresses only self-reactive immune responses. Such a therapy would, ideally, be efficacious without compromising the body's ability to fight off infections. Several autoimmune diseases appear to be caused in large part by Th1-driven inflammation. Examples include type 1 diabetes, multiple sclerosis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, and posterior uveitis. While the Th1/Th2 paradigm has evolved somewhat since its first description in 1986, it is still generally accepted that Th1 and Th2 responses have the ability to counter regulate each other. In particular, IL-4 suppresses differentiation of naïve T-cells into Th1 cells, resulting in decreased Th1 cytokine production and decreased Th1 cell proliferation in response to Th1-inducing antigens. In addition to Th2 responses, immunoregulatory networks can also suppress Th1 responses. These mechanisms include downregulatory cytokines such as IL-10 and TGFb, and regulatory cells such as T-regulatory cells and B-regulatory cells. Thus, there is a need for new treatment modalities that selectively down regulate Th1 responses.
Other therapies have also become available which use exposure to parasitic worms to treat or prevent hyperinflammatory diseases. To date, two types of parasitic worm-mediated therapy have been used in human clinical trials—Trichuris suis (pig whipworm) to treat ulcerative colitis and Crohn's disease, and live hookworm to treat allergies. While the exact mechanism(s) by which parasitic worms protect against inflammatory diseases is not completely understood, evidence suggests that parasitic worms induce strong immunoregultory signals. Patients exposed to parasitic worms demonstrated increased IgE antibody levels, increased numbers of circulating basophils and eosinophils, and increased IL-10 production which can suppress excessive inflammatory responses.
However, a number of factors have limited the widespread use of parasitic worm infections in commercial therapeutic applications. Not only might patients potentially express concern about being infected with parasitic worms, but if so infected, they incur the risk of suffering from pathology induced by live worm infection. Additionally, the use of animal hosts to cultivate parasitic worms can compromise batch purity and homogeneity during production. Due to the complex life cycle of parasitic worms, it is also often difficult to obtain sufficiently large quantities of antigen necessary for commercial therapeutic applications. Thus, there is also a need for new treatment modalities that can suppress excessive inflammatory responses without the risks associated with parasitic infections.